Spectrum of Central Nervous System Involvement in Childhood-Onset Sjögren’s Syndrome: A Case-Based Review

Sjögren’s syndrome (SS) is less frequently diagnosed in childhood than in adults, and central nervous system (CNS) disease is among the rarest systemic involvements. Thus, the clinical spectrum of CNS diseases and their management strategies have not been fully defined. In this article, we present the case of a 16-year-old girl who was referred for severe headache and diagnosed with SS with CNS involvement. Several immunosuppressive treatments failed to improve her neurological symptoms until the rituximab treatment. When we systematically reviewed the literature on cases of CNS involvement in childhood-onset SS, we found that CNS involvement was the presenting feature at the diagnosis of SS in the majority of published cases. While headache and fever were the most frequent complaints at presentation, most of the children displayed features of neuromyelitis optica spectrum disorder. CNS disease showed a variable response to immunosuppressives, and residual neurological deficits were not rare. Additionally, a significant number of cases required treatment with rituximab due to the treatment failures or subsequent flares. Sjögren’s syndrome should be considered in children presenting with predominant neurological symptoms, and careful evaluation of glandular features might help in the prompt diagnosis of childhood-onset SS in children with CNS disease.


INTRODUCTION
Sjögren's syndrome (SS) is a chronic systemic autoimmune disease that mainly affects the exocrine glands with lymphocytic infiltration and B-cell hyperactivity. 1 Involvement in other organ/systems such as the kidney, liver, lung, endocrine glands, nervous system, muscle, joint, or inflammation of the vessel wall might be seen in association with the disease, which is referred to as extraglandular involvement.Central, peripheral, and/or autonomous nervous system involvement can be seen in association with SS, and peripheral nervous system involvement is more common than central nervous system involvement. 2Neurological manifestations of SS account for 20% of all SS cases, and central nervous system (CNS) involvement is seen in 1-5% of cases, most commonly as neuromyelitis optica spectrum disorder (NMOSD). 3Childhood-onset SS accounts for 5% of all cases, and CNS involvement and NMOSD have been reported in 2% of children with SS. 4,5 Thus, the spectrum and features of CNS diseases NEUROSJÖGRENS in children with SS are not well-defined.Here, we present a case of SS-related CNS involvement and review the literature to identify the spectrum of CNS disease, treatments, and outcomes in childhood-onset SS.

CASE REPORT
A 16-year-old female patient was referred to us for the evaluation of autoimmune diseases due to a severe headache.Complaints of headache started a year ago, gradually worsened, and impaired her sleep.Additionally, she reported fatigue, joint pain with morning stifness in the hands, Raynaud's phenomenon, and dry mouth and eyes.The patient was of Afghan origin and had no known rheumatic disease in her family.Physical examination, including detailed neurological assessment, was normal, and no active arthritis was observed.On laboratory examination, the complete blood count was normal without any cytopenia, and acute phase responses were within normal limits.The patient's immunoglobulin M (IgM) level was high (2.5 g/L) and other immunoglobulin subclasses were normal.In addition, a low complement C4 (0.08 g/L) was observed with a normal complement C3 level.The rheumatoid factor level was within the normal range, and cryoglobulin levels were not studied.Anti-nuclear antibody was positive with a titer of > 1/1000, but no specific autoantibody was detected in the extractable nuclear antigen panel, including anti-dsDNA, anti-Sm, anti-SSA, anti-SSB, and anti-centromere antibodies.Owing to the symptoms of dryness, a Schirmer test was performed, which revealed severe dry eyes (< 5 mm) in both eyes.In addition, heterogeneity was observed in salivary gland ultrasound.Magnetic resonance imaging (MRI) of the brain revealed multiple small hyperintense lesions in the white matter on T2 weighted images which might be compatible with a demyelinating process or vasculopathy.The patient was diagnosed as CNS involvement of Sjögren's syndrome, and prednisolone (0.5 mg/kg) with azathioprine treatment was initiated.During follow-up, the patient demonstrated vasculitic rashes in the upper extremities, and the CNS symptoms were not responsive to the initial treatment.Cyclophosphamide with pulse methylprednisolone was employed but patient continued to experiance severe headache.Thus, treatment with rituximab was initiated with mycophenolate mofetil as maintenance therapy.Following the administration of rituximab, the patient's symptoms disappeared, including fatigue, steroid treatment was withdrawn, and serum complement levels returned to normal.Over a one year period after rituximab treatment, the patient did not display any extraglandular disease manifestations.

SEARCH STRATEGY
We aimed to identify case reports or case series of children with childhood-onset Sjögren's syndrome associated with CNS involvement in the English language.Records were identified from PubMed, Web of Science, and Scopus databases on May 7, 2023.The terms used were "Sjögren" AND "child" AND "nervous system", and "Sjögren" AND "child" AND "cns".The initial search revealed 356 records.After the removal of duplicates, titles and abstracts were screened to exclude irrelevant papers, abstract-only publications, and adult cases.Eleven articles remained after the review and additional relevant articles were identified from the reference lists of the papers.After the review, nineteen published cases of childhood-onset CNS disease, associated with SS, were identified (Figure 1).Age at onset, sex, glandular and extraglandular features, CNS disease characteristics, laboratory and imaging results, and treatments were retrieved from the publications.

DISCUSSION
Herein, we describe a case of an adolescent with Sjögren's syndrome and associated CNS involvement without any overt neurological findings.In addition, our literature review showed that despite almost half of the children displayed NMOSD, CNS disease in childhood-onset SS has a wide spectrum of features, including cranial nerve palsies, seizure disorders, aseptic meningitis, and  encephalopathy.In addition, a high rate of variability was observed among the treatment modalities, but rituximab was used in the majority of cases published after 2015.The most frequent symptoms in published cases were headache, fever, and weakness, and SS was frequently diagnosed at the onset of CNS disease.The disease characteristics of the published cases of Sjögren's syndrome are shown in Table 1 and Table 2. Childhood-onset Sjögren's syndrome can occur at any age and accounts 1-5% of cases. 3,25Unlike in adults, sicca symptoms were less frequently detected in children, and recurrent parotiditis might be the only presenting sign of glandular disease.Thus, in some children, diagnosis requires imaging and histopathological evaluation of glandular involvement. 26The most recent ACR/EULAR classification criteria for Sjögren's syndrome do not cover the full spectrum of childhood-onset disease, and children are less frequently evaluated for the features of the classification criteria. 25Similarly, our patient do not fulfill the classification criteria, but a glandular biopsy was thought to be unnecessary to conclude a diagnosis due to the classical picture of the disease in our case.Likewise, the majority of published cases of CNS disease displayed sicca symptoms.Thus, rigorous assessment of glandular features may improve the diagnosis of childhood-onset SS.Additionally, the majority of published cases display a positive anti-SSA antibody.Since, autoantibodies are evident before the development of symptoms in adults with SS, 27 it might be speculated that the features of SS might be evident before the onset of CNS disease in children.The association between NMOSD and SS is well known in adult-onset disease. 2,3Similarly, our study showed that almost half of the children with CNS involvement displayed the features of NMOSD.In addition, variable presentations such as aseptic meningitis, meningoencephalitis, and seizure disorders might be observed.Despite not being included in this systematic review, psychiatric manifestations associated with childhood-onset SS have been also reported. 28Studies have shown that low complement C3, male sex, anti-SSA, and kidney and pulmonary involvement might be associated with neurological involvement in adults with SS. 29,30 However, in published cases of childhood-onset SS, fever was the most common extraglandular feature, and other involvements such as kidney or lung involvement were rarely reported.In addition, hypocomplementemia was not frequently observed.Magnetic resonance imaging (MRI) has no place in the current diagnostic criteria for neurological manifestations of SS, but it is useful for narrowing the differential diagnosis.The most common presentation of Sjögren's syndrome on MRI, regardless of patient age, is periventricular or subcortical, focal and nonspecific, T2-hyperintense lesions. 31Similarly, the majority of published cases of chilhood-onset SS with CNS involvement displayed changes in intensity or abnormalities on T2-weighted MRI.Treatment of SS can be divided into two categories: relief of the main symptoms and treatment of severe systemic disease, and treatment should be personalised on a case basis. 32,33A recent systematic review showed that rituximab is most commonly used for the treatment of kidney and CNS diseases in childhood-onset SS. 34 Similarly, our study showed that rituximab was frequently employed in chilhood-onset SS with CNS involvement; however, these patients were also treated with a varying range of immunosuppressives with either treatment failures or flares, which resulted in the use of rituximab.The latest EULAR recommendations for the treatment of SS also state that systemic immunosuppressants should be used only in the presence of systemic disease.In addition, for the management of CNS disease, cyclophosphamide was favored over rituximab as the first-line treatment, especially for NMOSD and vasculitic presentations. 35espite the higher prevalence of SS in adults, the prevalence and association of residual neurological deficits have not been investigated in SS patients with neurological involvement.However, our study showed that residual neurological deficits are not uncommon in childhood-onset SS with CNS involvement.Interestingly, among the three cases with CNS involvement during the course of SS, only one required aggressive immunosuppression and developed neurological sequelae.In addition, complete neurological recovery is frequently reported in children receiving rituximab treatment.Thus, it can be speculated that early recognition of glandular disease, before the onset of CNS involvement might improve patient outcomes.In conclusion, while almost half of CNS involvement in childhood-onset SS shows features of neuromyelitis optica spectrum disorder, CNS disease displays a high degree of variability, such as aseptic meningitis and encephalopathy.In most children, diagnosis of childhood-onset SS is at the time of the CNS involvement.Thus, prompt diagnosis requires careful evaluation of glandular and serological features.The treatment response does not seem to be associated with the presence of prominent neurological symptoms, but it is important to keep in mind that CNS disease might result in a residual neurological deficits.A wide variety of agents are used for treatment, but they result in different success rates on a case basis.However, most children require treatment with rituximab, which seems to be effective in the treatment of CNS involvement.

INFORMED CONSENT
Written informed consent was obtained from the patient for the publication of this case report.

FUNDING
The authors received no financial support for the research, authorship, or publication of this article.

Figure 1 .
Figure 1.Flow chart of the litreature review.

Table 1 .
Clinical and laboratory features of childhood-onset Sjögren's syndrome reported in the literature.

Table 2 .
Features of central nervous system involvement, treatments, and outcomes of published cases with childhoodonset Sjögren's syndrome.

Table 2 .
Features of central nervous system involvement, treatments, and outcomes of published cases with childhood-onset Sjögren's syndrome.
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